High content screening of a kinase-focused library reveals compounds broadly-active against dengue viruses

• Published in: PLoS neglected tropical diseases Vol. 7; no. 2; p. e2073
• Main Authors: Cruz, Deu John M, Koishi, Andrea Cristine, Taniguchi, Juliana Bosso, Li, Xiaolan, Milan Bonotto, Rafaela, No, Joo Hwan, Kim, Keum Hyun, Baek, Sungmin, Kim, Hee Young, Windisch, Marc Peter, Pamplona Mosimann, Ana Luiza, de Borba, Luana, Liuzzi, Michel, Hansen, Michael Adsetts Edberg, Duarte dos Santos, Claudia Nunes, Freitas-Junior, Lucio Holanda
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.02.2013; Public Library of Science (PLoS)
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - isolation & purification; Antiviral Agents - pharmacology; Biology; Cell Line; Clinical trials; Dengue fever; Dengue Virus - drug effects; Dengue viruses; Drug Discovery - methods; Health aspects; Hepatocytes - virology; High-throughput screening (Biochemical assaying); High-Throughput Screening Assays; Humans; Infections; Methods; Microbial Sensitivity Tests; Pharmaceutical industry; Phosphotransferases; Technological change; Tropical diseases; Vaccines; Viral infections; Viruses; South Korea; Microbial Sensitivity Tests; Cell Line; High-Throughput Screening Assays; Hepatocytes; Humans; Antiviral Agents; Drug Discovery; Dengue Virus
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0002073

Dengue virus is a mosquito-borne flavivirus that has a large impact in global health. It is considered as one of the medically important arboviruses, and developing a preventive or therapeutic solution remains a top priority in the medical and scientific community. Drug discovery programs for potential dengue antivirals have increased dramatically over the last decade, largely in part to the introduction of high-throughput assays. In this study, we have developed an image-based dengue high-throughput/high-content assay (HT/HCA) using an innovative computer vision approach to screen a kinase-focused library for anti-dengue compounds. Using this dengue HT/HCA, we identified a group of compounds with a 4-(1-aminoethyl)-N-methylthiazol-2-amine as a common core structure that inhibits dengue viral infection in a human liver-derived cell line (Huh-7.5 cells). Compounds CND1201, CND1203 and CND1243 exhibited strong antiviral activities against all four dengue serotypes. Plaque reduction and time-of-addition assays suggests that these compounds interfere with the late stage of viral infection cycle. These findings demonstrate that our image-based dengue HT/HCA is a reliable tool that can be used to screen various chemical libraries for potential dengue antiviral candidates.